Abstract

Dopamine receptors play a critical role in reward-related learning but receptor subtypes may be differentially involved. D2-preferring receptor antagonists, e.g., haloperidol, attenuate acquisition of cocaine-conditioned motor activity at doses that fail to block expression. We compared haloperidol to the D3 receptor-preferring antagonist 2,3-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4] triazol-3-yisulfanyl)-propyl]-piperazin-1-y1}-pyrimidine hydrochloride (ABT-127), given at D3-receptor selective doses (i.e., no displacement of [3H]raclopride binding, no effects on gamma-butyrolactone-induced striatal L-DOPA accumulation; no attenuation of apomorphine-induced stereotypy). We hypothesized that haloperidol and ABT-127 will produce a doubly dissociable effect on acquisition vs. expression of cocaine-conditioned activity. Rats received three 1-hr habituation sessions to activity monitors followed by three 1-hr cocaine (10 mg/kg) conditioning sessions. The expression phase (no cocaine injections) took place 48 hrs later. Haloperidol (50 μkg) given during the conditioning phase blocked the acquisition of conditioned activity but failed to block the expression of conditioning when given on the test day. In contrast, ABT-127 (1.0 mg/kg), when given during conditioning failed to block the acquisition of conditioned activity but blocked the expression of conditioning when administered on the test day. Results suggest that D2 receptors are more critically involved in acquisition than initial expression and D3 receptors are more critically involved in expression than acquisition of conditioned activity based on cocaine.